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CHEM 221 section 52

LECTURE #07 Thurs., Feb.14, 2008

ASSIGNED READINGS:TODAY’S CLASS:

NEXT CLASS:

4.6, 4.7 in last day’s notes actually…4.8-4.11 Alkene reactions with different mechanisms

adding RCOOOH: to make epoxideadding HOH/R: oxymercuration, hydroborationadding hydrogen: to make alkanesadding HBr via radical mechanism

4.12 Introduction to synthesis

Midterm exam: Thurs. Feb.28th 6:00-7:15pm lecture afterwardscovers everything so far to end of Ch.4see samples on website

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4.9 Addition of a peroxyacid to an alkene: route to “epoxides” = reactive 3-memb. ring ethers

Mechanism: CONCERTED…

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Recall 4.5: Acid-catalyzed addition of H2O or ROH Markovnikov addition: occurs in acid; electrophile = H+

H2SO4, H2O

H2SO4, CH3OH

C+ int. rearrangements possible

Now: let’s compare a few ways to make alcohols…

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4.8 Oxymercuration-reduction: another Markovnikov way to add HOH / ROH to an alkene

Mechanism: rxn 1: via cyclic C−Hg+−C int. similar to halonium ion(complex) rxn 2: required to replace Hg with H…

Markovnikov addition: H goes where more H’s are

Advantages: gentle conditions & controllable results1. does not use acidic conditions safer for many other funct’l groups2. does not proceed via C+ int. no rearrangements

or ROH

Why know another route? Small-scale: can spend $ on rgts & disposal oxymercuration-redn usedIndustrial: need cheap reagents & disposal H+-cat additions used

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4.10 Addition of borane: hydroboration-oxidationanti-Markovnikov addition of water

Anti-Markovnikovaddition

ANTI-MARKOVNIKOV ADDITIONS: H adds where fewer H’s wereoccurs because B acts as the electrophile in the 1st step!

B—H bond adds across the C=Copen-shell, more electrophilic than H…

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Steps 2 &…: complicated oxidation by H2O2, OH−, H2Oremoves boron group & replaces with OH

(you are not responsible for the details here)

Step 1: C=C bond attacks δ + B at same time as δ − H attacks sp2 C• a concerted (1-step) process• thus: H & B on same side of C=C syn addition

“Syn”addition!

an alkylborane

MECHANISM OF HYDROBORATION

‡

or

REGIO: Electrophile adds to the less highly-substituted CWHY?

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MORE DETAILS: 1st steps = formation of alkyl boranes

In hydroboration, 1 BH3 actually reacts with 3 alkene molecules:

+ H—BH2

You are not responsible for reproducing this……but seeing the full mechanism will help you understand the rxn

First:

Second:

Third:

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& Next: Oxidation steps (↑ bonds to O): OH replaces B…

B still open-valence,so still a strongLewis acid…

a 1,2-alkyl shiftdisplaces OH−

(ok -- in basic solution)

alcohol

You are not responsible for reproducing this……but seeing the full mechanism will help you understand the rxn

peroxideWeak O-O bond

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Stereochemistry of Hydroboration–Oxidationi.e., relative orientation of groups in the products (see more in Ch.5)

Always syn addition: H & B add to same face of π-bondbecause this add’n is concerted, not step-wise

In addition step: H-B can add to either side of C=C initially,so get both possible syn products

Oxidation steps: do not change the orientation of the groupsthus: stereochemistry dictated by addition step

Coming soon in Ch.5: • How do we describe this type of isomer?• What is different about them? • What about the other rxns seen so far?

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Key synthetically useful features of hydroboration: 1.) adds H-OH with anti-Markovnikov regiochemistry2.) avoids rearrangements of molecule (no carbocation int.)

predictable, clean regiochemistry (good product control)

Acid-catalyzed hydration would involve 2° carbocation

would rearrangeTHUS:major product would be

2-methyl-2-butanol

…3-methyl-2-butanolas a minor product

Hydroboration productno rearrangementanti-Markovnikovsyn addition of H & OH

(syn not noticeable here since rxndid not generate stereochemistry)

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What products would these reaction conditions yield?

• E = ?• C+ ?

• Nu = ?

• E = ?• C+ ?

• Nu = ?

H2SO4

H2O

1.) BH3 / THF

2.) H2O2 / OH- / H2O

aromatic ringwill remain

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Which set of reagents would be the best choice to accomplish the transformation shown below?

a) H2SO4, CH3OHb) CH3OH, cat. H+

c) 1. Hg(OAc)2, CH3OH 2. NaBH4

d) 1. BH3, CH3OH, 2. H2O2, CH3O-

e) either A or B

4.5 -4.10

OCH3

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4.11 Relative stabilities of alkenesdetermined from rates of rxn with H2

H

H

H2

metal catalystCommon catalysts: nickel (Ni), Pt/C, Pd/C

= platinum or palladium-impregnated graphite“platinum on carbon”, “palladium on carbon”

Exact Mechanism of hydrogenation not known, but is roughly like this:

HYDROGENATION:

Fig. 4.5

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Heats of hydrogenation (∆Hrxn for alkene + H2 / cat) provide a measure of relative E of alkene isomers

three isomers:3-methylbutene2-methylbutene2-methyl-2-butene

H2

Pt/C

All yield same product:2-methylbutane + HEAT

More heat released MUST mean original alkene was less stable…

Fig. 4.6

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The result: stability varies with substituent # & location

Terminal alkenes less stable than isomeric internal alkenes: sterics…

Internal alkeneTerminal alkenes

Most stable

Least stable

And remember: extended π-systems are REALLY stable (delocalized…)

Relevance? Predicting regiochemistry of rxns that form alkenes: Ch.9major product is usually the more-stable alkene

< < <

<≈

More highly substituted alkenes are generally more stable: ∆HH2n data

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Rank the following compounds in order of decreasing stability (from most stable to least stable).

a) 1 > 2 > 3 > 4b) 1 > 2 > 4 > 3c) 4 > 1 > 2 > 3d) 4 > 3 > 2 > 1e) 2 > 4 > 1 > 3

4.11

1 2 3 4

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Which of the following compounds will react most readily (i.e., fastest) with HCl?

4.4, 4.11

1 2 3 4 5

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11.3, 11.6 Addition of Radicals to Alkenes:Anti-Markovnikov addition of H-Br

hν or ∆

Markovnikovadditionproduct

Anti-Markovnikov

addition!

Choose rxn conditions that yield desired regiochemistry:a) HBr at RT in the dark Markovnikov additionb) HBr with heat or light anti-Markovnikov addition

(+peroxide)

RADICAL HYDROBROMINATION: opposite regiochemistry

Normal hydrobromination:

Note: this trick only works with HBr (no regio. change for HCl or HI)

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Relative stabilities of alkyl radicals: same trend as C+s, for same reason

methyl radicalCH3

Hydrobromination with peroxide:proceeds via a radical intermediate

stability: 3° > 2° > 1° >> methylC centre is sp2-hybridized (like C+)

IMPLICATIONS of radical intermediate:

1. regiochemistry: radical centre (& later H) will be on more subst’d C2. stereochemistry: racemization (if chiral) see this in Ch.5

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Mechanism: Addition of radicals to alkenes

• Form the 1st reactant radicals• Good radical initiators

= organic peroxides (ROOR) weak O-O bond homolyticallycleaves under heat or light

Form radicalintermediatesthat propagate radical chain rxnDesired product

hνor ∆

More stableof 2 possible

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…Mechanism: Addition of radicals to alkenes

Radical-coupling rxnsdo not generatenew radicals

Side product:dihalide

Summary: Radical hydrobromination• anti-Markovnikov HBr addition: via more stable radical intermediate• use dilute solution: to minimize dimerization of radical intermediates• use an inert solvent: usually CCl4 or benzene; never a “protic” solvent!And after Ch.5, you’ll see…• racemized alkyl halide product: if chiral centre created…

Side product:dimer

(i.e., 2 units coupled)

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Addition rxns:use π-bond to add a new functional group

4.12 Reactions and synthesis

We’ve seen how to control:

functionality: identity of new group(s)whether attach 1 group only vs 1 each side

regiochemistry: which site new group attaches at

stereochemistry: relative 3D orientation of groups (Ch.5…)

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How could this compound be synthesized from an alkene?

Why should 3-methylcyclohexene NOT be used as a starting material to make the above compound?

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Summary of alkene rxns: what can we make starting from here?

MARKOVNIKOV ADDITIONS ANTI-MARKOVNIKOV ADDITIONS

Pd/CPt/Cor Ni ALKANES

ALKYLHALIDES

HALOHYDRINS

VICINAL DIHALIDES

ALCOHOLS

ETHERS

STARTING WITH AN ALKENE• Can add electrophiles

EPOXIDES

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What reagents should we use to perform the following synthetic transformations?

AB

C

DE

F

G

H

OH

Cl

Br

Br

Br

OH

OCH2CH3

Br

OH

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Chapter 5: StereochemistryChapter Goals: To understand the importance of permanent differences

in the spatial arrangement of atoms in molecules.Learn to identify different types of isomers.Understand symmetry and chirality, and their implications. Understand stereochemistry of reactions.5.1 Cis-trans isomers5.2 Chirality5.3, 5.5 Asymmetric carbons, chirality centres, and stereocentres5.4 Isomers with one asymmetric carbon5.6-5.7 Drawing & naming enantiomers5.8-5.10 Optical activity, optical purity & enantiomeric excess5.11-5.13 Isomers with more than on asymmetric carbon5.14 Rxns of compounds that contain an asymmetric carbon5.15 Absolute configuration5.16 Separating enantiomers: in the lab, & biologically5.17-5.18 covered in more advanced courses5.19 Stereochemistry of electrophilic addition rxns of alkenes5.20-5.21 Stereochemistry of enzyme-catalyzed reactions

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To classify relationship between any 2 isomers… Isomers

• Same connectivity of atoms• Different 3D arrangement

• Differentconnectivity

= THE SAMECOMPOUND

• Interconvertvia rotation of σ –bonds

= Geometric isomers• Must break bonds

to interconvert

• Not mirror images • Mirror images• All stereocentres have

opposite configuration

• Same formula

• Alkenes• Cyclic? see

• ≥ 2 stereocentres• Only some have opposite configuration

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Classification of Isomers1. Constitutional isomers: different connectivity

e.g. 1-butane and methylpropane (i.e. isobutane)

SUBTYPES:

(a) Positional isomers: different position of functional groupse.g. 1,2-dichlorobenzene & 1,3-dichlorobenzene

(mp 183 °C) (mp 172 °C)

(b) Functional isomers: different functional groupssame bulk formulas but very different propertiese.g.

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b) Isomers that contain asymmetric atoms: next…

“Configurational isomers”actually different compounds (definitely isolable)to interconvert them: must BREAK covalent bonds

a) cis/trans isomers: arrangement around C=Cor relative orientations on a ring

2. Stereoisomers: same connectivity, but different arrangement of atoms in space(permanently different 3D orientation)

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Isomers are NON-identical…

To be isomers, molecules must not be identical.- check: are they just different conformations?

The test for "identicality": can they be superimposed??

TECHNICALLY SPEAKING: conformers are isomers

IN PRACTICE: Usually non-isolable (cannot isolate them)…

THEREFORE: conformers not usually considered isomers: treat them as IDENTICAL

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109.5o

Carbon is tetrahedral: Consequences…

EXAMPLE #1EXAMPLE #1::Td C with Td C with one one substituentsubstituent(CH(CH33XX))

2 molecules of CH2 molecules of CH33XX

Identical molecules!Identical molecules!(can be superimposed(can be superimposed……))

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Carbons with two different substituents still have two substituents that are the same… ∴ symmetric

EXAMPLE #2EXAMPLE #2::Td C with Td C with TWO TWO substituentssubstituents(CH(CH22XXYY))

2 molecules of CH2 molecules of CH22XXYY

Identical molecules!Identical molecules!(can be superimposed(can be superimposed……))

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If two molecules are non-superimposable

mirror-images of each other:they have

opposite “configuration”The two molecules are called

“ENANTIOMERS”(Greek enantion = opposite)

Carbons with 4 different groups are “asymmetric”

Td C with THREE Td C with THREE substituentssubstituents (CH(CHXXYYZZ))

NOT all CHXYs are identical (non-identical if non-superimposable)

AND cannot besuperimposed

They are mirror images

THEREFORE: differentcompounds

Sometimes 2 CHXYs ARE superimposable (∴ identical)

These molecules are described as being “handed” or “CHIRAL”

(Greek cheir = hand)

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Why does your right hand not fit properly in your left glove?ANS: because hands are chiral.

5.2 Chirality: “Chiral” things are asymmetric

Right and left hands are mirror images.They are not superimposableTo convert your right hand into your left hand, you would need to:

remove your thumb & move it to other side of palm(and your fingers too actually)

Anything with a non-superimposable mirror image is CHIRAL.

they have opposite configuration!

Anything with a superimposable mirror image is ACHIRAL.HINT: look for internal planes of symmetry

• any object (or molecule) with a mirror plane within itcan be superimposed onto its own mirror image

is symmetric, ∴ achirale.g., human body (as viewed from the outside)

HINT: all chiral objects are inherently asymmetrice.g., hands, feet

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Two ways to evaluate a molecule, or any object, as being ACHIRAL …if it’s not achiral, it’s chiral…

1.) Does it have a plane of symmetry? If YES achiral2.) Does it have a superimposable mirror image?

If YES achiral

Cyclohexanol

Superimposablemirror image

achiral!

Plane of symmetryachiral!

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Key stereochemical terms: CHIRALITY“Chiral” describes objects that are not superposable on their mirror image, i.e., objects that have “handedness”

Achiral is thus used to described the lack of chirality

A plane of symmetry is an imaginary plane passing trough an object, dividing it so that one half is the mirror image of the other one

A centre of symmetry is a point so situated that identical components of an object are located on opposite sides and equidistant from that point along any axis passing through it

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Are the two products of this reaction… chiral?different?

Learn soon how to describe they way they are related.

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ASSIGNED READINGS

BEFORE NEXT LECTURE:

Read: rest of Ch.4 & 11.3, 11.6

Practice: predicting products for given reactantsidentifying reactants for desired productswriting full mechanisms (arrow pushing!)

including C+ rearrangements…

Midterm exam: Thurs. Feb.28th 6:00-7:15pm lecture afterwardscovers everything so far to end of Ch.4see samples on website